While lead poisoning has been extensively studied, exposure levels remain elevated in many vulnerable populations. Other toxic metals such as arsenic and manganese are also elevated in the environment, but their effects on neurodevelopment are poorly understood. Perhaps more importantly, the effects of mixed metal exposures are pooriy understood, yet this exposure scenario is most reflective of the real worid. In this project we will pool the data and resources from 3 cohort studies of metals and neurodevelopment. One in a developing country-Bangladesh, where metal exposures are unusually high, one in Mexico, a middle income country where metal exposures are moderately high, and one in a developed Country-Tar Creek, OK, where exposures are representative of a community near a US toxic waste site. These cohorts allow us to overcome barriers that prevented research in both metal mixtures and the role of developmental windows in neurotoxicology. Our program will have a final sample size of 2600 children with prospective data on metal exposure, and repeated neurophenotype measures. This will give us sufficient power to model the effects of joint exposures to As/Pb, As/Mn and Mn/Pb and their 3 way interactions on neurodevelopment. In addition, as we have longitudinal exposure data, we can compare the effects of metal exposure during different developmental windows (i.e. pre vs post-natal exposure) on neurodevelopment. This project is also integrated with the nonbiomedial projects. For example, we will partner with projects 4 and 6 to test the effect of deep wells on As/Mn biomarker levels in Bangladesh. We will also partner with Projects 5 and 6 to validate statistical methods for site characterization and the incorporation of bioavailability/metal speciation data into geospatial models of exposure assessment at the Tar Creek Superfund site.